The complex cellular and molecular interactions that function pathogenically in human synovial inflammatory diseases such as rheumatoid arthritis remain only partially understood. We have recently demonstrated a previously unappreciated critical role for mast cells in the K/BxN serum transfer model of inflammatory arthritis. However, the precise mechanisms by which synovial mast cells are activated and the mediators of inflammation elaborated by this cell population are unknown. This specific goals of this proposal are: 1) to define the mechanisms of synovial mast cell activation and 2) define the inflammatory mediators produced by synovial mast cells that contribute to arthritis. This proposal will utilize both in vitro cellular and molecular techniques and in vivo genetic approaches to elucidate the mechanisms by which synovial mast cells participate in synovial inflammation. These analyses will shed light on pathogenic mechanisms relevant to human inflammatory arthritis such as rheumatoid arthritis. It is likely that further understanding of synovial mast cell participation in arthritis will open new avenues of treatment for these diseases. Furthermore, these studies will expand our understanding of mast cell biology in inflammatory responses.